The Mayo Clinic SPORE in Pancreatic Cancer has built a robust environment to facilitate high quality research by our talented investigators. Our goal is to apply innovative technologies and resources in basic/clinical/population research to achieve the best strategies for prevention, early detection and therapy and increase survival of this devastating malignancy. The SPORE aims to: 1) Provide the scientific leadership and organization to sustain and support outstanding translational pancreatic cancer (PC) research; 2) Provide the organizational infrastructure to facilitate communication and promote interactions among SPORE investigators and the larger research community; 3) Provide resources to develop innovative research projects in translational PC research; 4) Foster career development in translational PC research; and 5) Assure excellence of research through a rigorous internal review process of the SPORE research programs and projects, with periodic review and support from a panel of outstanding external advisors. We have developed a responsive infrastructure that has spawned innovative research and interdisciplinary interactions, attracting committed investigators. Mayo Clinic sees -725 PC patients yearly, constituting 1.7% of all PC cases in the US. Four cores (Administrative, Biostatistics, Clinical Research, and Tissue) will provide support. Project 1 (new) will identify NFATs and NFAT-dependent target genes and roles, and conduct a Phase I study using cyclosporine A and gemcitabine-abraxane. Project 2 (new) will establish the role of NAD in PC, and use small molecule SIRT1 activating compounds in preclinical studies as well as a Phase I trial using SRT3025 with gemcitabine and abraxane. Project 3 (continuing) will use pursue findings that activation of innate immunity and chemotherapy can synergize curatively against pancreatic cancer, perform Phase l-ll trials which combines the TLRS agonist VentiRx-2337 with cyclophosphamide as second line therapy after FOLFIRINOX, optimizing a vaccine against PC-associated MUC1. Project 4 (new) will identify roles of DNA repair in PC and target patients with double-stranded DNA repair defects for individualized treatment in a Phase II study of the PARP inhibitor rucaparib in chemotherapy refractive PC.